Melanoma
The incidence of melanoma in most developed countries has risen faster, over the past 50 years, than any other cancer type. (Houghton A N, (2002) Cancer Cell; 2:275-278.) Approximately 45,000 new cases of melanoma are diagnosed each year in the United States, of which about 20% will eventually die secondary to metastatic disease. (Buzaid, A C. (2002) Crit Rev Ocol Hematol 44:103-108.) The prognosis for treatment of advanced melanoma is poor, with patient survival dictated primarily by the pace of progress of the disease. (Buzaid, supra.) Surgical intervention remains the most effective treatment option, but only if the disease is diagnosed and treated in its earliest stages. (Molife R et al. (2002) Crit Rev Oncol Hematol 44:81-102.) Hence, survival chances are excellent if melanoma is diagnosed and surgically removed in its earliest stages. Each successive stage of disease progression, however, witnesses a significant drop in the chance for survival as the risks of relapse and recurrence increase. (Molife et al, supra.) Thus, there is a need for new, more effective methods of treatment that are distinct from surgical intervention or enhance the efficacy of surgical intervention.
Clinical response rates to treatment are typically lower in patients with melanoma than in patients with other cancers. Clinical trials have shown malignant melanoma to be highly resistant to both chemotherapy as well as radiation treatment. A durable response rate of only about 10% was observed following current treatment modalities. (Flaherty L E et al. (2002) Semin Oncol 29:446-455.) An evaluation of biochemotherapy in previously treated patients documented a 6% response rate. (Chapman, et al. (2002) Melanoma Res. 12:381-387.)
The lack of therapeutic response to the existing treatment protocols for melanoma, is due largely to its cellular, biochemical, and molecular origins. (Ichihasyhi N et al. (2001) Br J Dermatol 144:745-750; Heere-Ress et al. (2002) Int J Cancer 99:29-34; Sinha P et al. (2000) Electrophoresis 21:3048-3057.) Melanomas arise from a very specific cell lineage: they are the product of the malignant conversion of melanocytes, which are themselves derived originally from mesenchymal neural crest cells. In contrast, carcinomas arise from the malignant conversion of epithelial cells. Furthermore, melanomas are not sex hormone dependent, while many carcinomas are (e.g., androgen-dependent prostate cancer and estrogen-dependent breast). Additionally, melanomas carry out the process of melanogenesis, while carcinomas exhibit this process rarely, if ever. One or more of the characteristic properties of melanomas must account for the resistance of melanomas to existing treatment protocols.
Melanogenesis
Melanogenesis is the process of synthesizing of melanin, which is responsible for cell pigmentation. Melanocytes, located in the skin, hair follicles, stria vascularis of the inner ear and uveal tract of the eye, are the cells of origin for melanomas and exhibit melanogenesis. Melanogenesis is a complex biochemical process initiated by the hydroxylation of the amino acid L-tyrosine, which results in the formation of L-dihydroxyphenylalanine (L-DOPA). L-DOPA is converted, in turn, to Dopachrome by the action of a specific melanocyte-associated enzyme: tyrosinase. Further oxidation and reduction reactions ultimately convert Dopachrome to melanin.
Studies have indicated that melanogenesis is associated with the enhanced resistance of pigmented melanoma cells to radiation therapy and to chemotherapy. (Kinnaert E et al. (2000) Radiation Res 154:497-502; Slominski A et al. (1998) Anti-Cancer Res 18:3709-3716.) These treatments are thus rendered ineffective against melanotic melanoma. A method to block melanogenesis would provide a clinically useful approach to render melanoma cells more sensitive to both chemotherapy and radiotherapy.
Studies have also shown that many of the intermediate products produced during melanogenesis have toxic effects. (Slominski A et al. (1998), supra; Riley P A (1991) Eur J Cancer 27:1172-1177; Prota G et al. (1994) Melanoma Res 4:351-358.) Intermediates of melanogenesis can contribute to, for example, immunosuppression, fibrosis, and mutagenesis. Inhibition of melanogenesis will therefore enhance the efficacy of cancer treatments that require participation of the host's immune system, e.g., the killing of melanoma cells damaged by radiation or chemotherapy.
para-Aminobenzoic Acid
para-Aminobenzoic acid (PABA) has been commonly used in sunscreens for its capacity to absorb ultraviolet radiation. PABA has also been used in clinical trials for the treatment of connective tissue diseases (e.g. scleroderma; dermatomyositis) and in combination with salicylates for the treatment of rheumatic fever. U.S. Pat. No. 6,368,598 (the '598 patent) suggested the use of PABA as a non-essential part of a linking group in a drug complex for the treatment of prostate cancers. As set forth in the '598 patent, the function of PABA is to act as a leaving group that is separated from the cytotoxic therapeutic portion of the drug complex by the action of enzymes present at the site of the intended therapeutic action. There is no suggestion, however, that PABA has any anti-tumor activity or other therapeutic function on prostate or other types of cancer. According to Holt, PABA can increase methotrexate levels, activity, and side effects. (Holt GA (1998) Food & Drug Interactions. Chicago: Precept Press, 170.)
para-Aminomethylbenzoic acid (PAMBA), a methylated derivative of PABA, has been found to be useful as a proteinase inhibitor for reducing the invasiveness of transplantable melanoma metastases in hamsters (Zbytniewski Z, et al. (1977) Arch Geschwulstforsch 47:400-404). The action of PAMBA is to inhibit proteolysis by extracellular proteases, thus preserving the extracellular matrix as a physical barrier that reduces the invasiveness of cancer cells. Reducing invasiveness, however, does not inhibit the growth of an established metastatic tumor. There is no suggestion therefore that PAMBA inhibits the growth of primary or metastatic melanoma. Nor is there any suggestion that PAMBA inhibits melanogenesis, or that it can enhance the effect of radiation or the activity of chemotherapeutic agents known to be useful in treating melanoma.
Accordingly, primary and metastatic melanoma continue to be difficult to treat with existing therapies. There is therefore a continued need for new effective treatments for these conditions. It has now been surprisingly discovered that PABA acts as a potent inhibitor of melanogenesis and can be used to treat melanoma effectively when administered alone or in combination with other anti-cancer modalities such chemotherapy and radiation. This finding is surprising because melanoma has different cellular origins from other cancers, including other skin cancers, melanoma is known to be highly resistant to treatments such as chemotherapy and radiation, and because the concentrations of PABA that inhibited melanoma cell growth in vitro and in vivo were found to have the opposite effect of enhancing growth of a lung carcinoma.